I11 n = 1, m = 18

I11 n = 1, m = 18. IV n = 2,m = 16. V n=5,m=10. VI n = m = 7. In the present paper there is reported the synthesis of four higher molecular weight aci...
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[COXTRIIBUTION FROM

THE

LABORATORY OF

CHEMICAL

THE

UNJVERf3ITY

OF

CALIFORNIA]

BRANCHED-CHAIN FATTY ACIDS. IX. SYNTHESIS OF ACIDS WITH SYMMETRICAL END-GROUPS JAMES CASON

AND

WILLIAM L. STANLEY'

Received September 10, 1948

In the preceding paper (1) of this series, there was reported the synthesis of a Cls acid (I) and a Clo acid (11) with symmetrical end-groups in which the branching groups were ethyl. These acids proved to have melting points more than twenty-five degrees below those of the normal isomers. CHa-( CHz),

CHr-(

I n = 1 , m = 12 I1 n = 1 , m = 13 I11 n = 1, m = 18

\ CH-( /

CH2)m-COzH

IV n = 2 , m = 16 V n=5,m=10 VI n = m = 7

In the present paper there is reported the synthesis of four higher molecular weight acids with symmetrical end-groups: 20-ethyldocosanoic acid (111), 18-n-propylheneicosanoic acid (IV), 12-n-hexyloctadecanoic acid (V), and 9-noctylheptadecanoic acid (VI). The melting points of these acids, respectively, are 64.8--65.5", 51.9-52.2", 28.3-28.7", and 9-14". It is seen that as the branching group becomes larger the melting point drops progressively further below that of the normal isomer, and is lowest for the CZsacid, VI, in which the tertiary carbon carries three chains of equal length. Thus, any apparent symmetry about the tertiary carbon does not tend to raise the melting point, but the melting point becomes progressively lower as the branching end-group becomes larger. As the tertiary carbon is shifted further toward the carboxyl, thus shortening the chain carrying carboxyl, the melting point must begin to increase again a t some point, for didodecylacetic acid (2) melts about 17" below the normal isomer. It is of interest that in the series of branched-chain alkanes synthesized by Whitmore, Sutherland, and Corby (3), the melting point again becomes progressively further below that of the normal isomer as the tertiary carbon carrying two of the same group approaches the center of the chain. Of the types of acids which it was previously suggested (4) might have melting points within the "excluded region" of about ten degrees below the melting point of the normal isomer, there have now been eliminated all but the acids having on a quaternary carbon either four groups of equal size or three equal groups and 1 Holder of a United States Rubber Company Graduate Fellowship in Chemistry a t the University of California, 1947-48. Present address : Western Regional Research Laboratory, Albany, California. 137

138

JAMES CASON .4ND W. L. STANLEY

the carboxyL2 Further attempts to prepare acids of this type are in progress; however, such acyclic acids of high molecular weight have not yet been found in nature. It seems likely that acids from natural sources with melting points in the "excluded region" are mixtures. There has already been presented (5) convincing evidence that two acids from tubercle bacillus, which melt in this region, are mixtures of normal isomers rather than homogeneous substances. The two symmetrical acids reported in the previous paper (1) were prepared by chain extension of the commercially available 2-ethyl-1-butanol, but alcohols with larger symmetrical end-groups are not available. Those required for synthesis of acids, I11 and IV, were prepared by high-pressure hydrogenation of unsaturated esters obtained by the illustrated sequence of reactions. OH RMgX

+

R C - ( C H Z ) ~ - C O ~ C ~ H K--+

/I

0 VI1 R VI11 R IX R X R

%

RL-(CH~)~-CO~CZHI

I

R = = = =

i

C2H6, n = 8 n-C3H7, n = 7 n-CsHl3, n = 10 n-CBH1,, n = 7 H2 ,CuCr

RCH-(CH2)n-CHnOH

12,

180-190"

mixture of unsaturated esters

I

R

1H2, Pt

XI R = C2H6, n = 8 XI1 R = n-CaH7, n = 7

RCH-(CHz),-COsC1Hs

R XIII R = n-CsHia, n = 10 XIV R = n-CsHI?, n = 7

The carbon chains of alcohols, XI and XII, were extended as before (1) by reaction of the corresponding cadmium reagents with the appropriate ester acid chlorides. The resultant keto esters, XV and XVI, were converted to the desired branched-chain acids (111,IV) (CzH,),CH-(CHz),-C-(CH2) 8-CO2 C2H6

/I

0

xv

(C~H~)ZCH-(CH~)~-C--(CH~),-CO~C~H~

II

0 XVI by Clemmensen or Wolff-Kishner reduction of the keto group.

* There has just appeared [Sperber, Papa, and Schwenk, J . Am. Chem. Soc., 70, 3091 (1948)l a report of synthesis of trialkylacetic acids with three of the same alkyl group. Although tri-n-propylacetic acid melted a t 65.&67.5", tri-n-butylacetic acid melted at 35.537.5", and tri-n-amylacetic acid presumably was an oil since no m.p. was reported. Thus, i t appears that high molecular weight acids of this type do not haveirelatively high melting points. (Footnote added Oct. 12, 1948).

BRANCHED-CHAIN FATTY ACIDS.

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139

For s,ynthesis of acids, V and VI, no further chain extension was necessary. The unsaturated esters obtained from keto esters, I X and X, were hydrogenated at low pressure with platinum catalyst, and saponification of the resultant saturated esters (XIII, XIV) gave the desired acids (V, VI). Ethyl 12-ketooctadecanoate (IX) was prepared by esterification of the keto acid obtained by oxidation of crude 12-hydroxyoctadecanoicacid from saponification of hydrogenated castor oil. The keto acid was separated with difficulty from stearic acid present in the hydrogenated castor oil, but the ethyl ester (IX) was easily purified by fractional distillation. The other three starting keto esters (VII, VIII, X) were prepared in good yield by reaction between the appropriate dialkylcadmium reagent and ester acid chloride. Since the next step in the synthesis is reaction of the keto ester with the same Grignard reagent used for making the cadmium reagent, it was thought possible that an easier approach to the hydroxy ester would be reaction of the Grignard reagent directly with the ester acid chloride, according to the following scheme.

OH 2RMgBr

+

ClC--(CH&-C02C2Ha

+

/I

22

I I

RC-(CH2),-C02C2Hs

R Unfortunately, considerably lower over-all yields were obtained by this procedure, for the reactivity of the acid chloride group toward the Grignard reagent is only slightly greater than the reactivity of the ester group. In the preparation of 10-ethyl-1-dodecanol (XI), the over-all yield based on o-cnrbethoxynonoyl chloride (the more valuable starting material) was 49Y0 in the process proceeding by way of preparation and isolation of the keto ester, but only 18% when the ester acid chloride was treated directly with the Grignard reagent. The selective reaction of a Grignard reagent with a keto ester to give a hydroxy ester has previously been used (6) as an approach to branched-chain acids. The over-all yields of saturated branched-chain acids or esters have been in the range, 20-44y0. A major difficulty has been the unstirrable mass obtained in the Grignard reaction. Since the yields in preparation of y-valerolactones (7) by a nearly identical process were doubled by addition of benzene t o break up this unstirrable mass, this device was tried in the present work. Results were favorable, in that the over-all yields of saturated esters (XIII, XIV) or saturated alcohols (XI, XII) were in the range, 39-5570. It wouid seem that an additional improvement in this process might be realized by introducing steric hindrance around the ester grouping. This possibility was investigated by the preparation of cyclohexyl 12-ethyloctadecenoate starting with ethylmagnesium iodide and cyclohexyl 12-ketooctadecanoate. The over-all yield of this unsaturated ester was 73%. By hydrogenation and transesterification, an over-all yield (based on keto ester) of ethyl 12-ethyloctadecanoate (XVII) amounting to 54% was obtained. C gHi 3CH-( CH2) io-CO2 C2H6

0

I

C2H6 XVII

140

JAMES CASON AND F.L. STANLEY

Thus, the use of the cyclohexyl ester appears an advantage, although the increase in boiling point is a handicap with higher molecular weight compounds, and trans-esterification is necessary if hydrogenation is carried out in ethanol. A major problem encountered in synthesis of pure compounds by the scheme used in the present work is separation of the large number of compounds obtained from the reaction between a Grignard reagent and a keto ester. When the saturated alcohol (XI or XII) is the desired end-product, there must be considered the separation of (a) the diol, A, from hydrogenation of the starting keto ester; (b) the alcohol, B, from hydrogenation of the unsaturated ketone resulting from dehydration of the keto alcohol arising from reaction of the Grignard reagent with both keto and ester group; (c) the hydrocarbon, C, arising from reaction of three moles of Grignard reagent with the keto ester, dehydration and hydrogenation. The diol, D, arising from reaction of only one mole of Grignard reagent with the ester group and no reaction with the keto groups would be expected in very small amount.

OH

OH

I

RCH-( CH2)n-CHZOH

I

RZCH-(CH2),-CHR

B

A

OH R,,CH-( CHs)n-CHRs C

OH

I

I

R CH-( CHz),-CHR

D

From a consideration of the contribution to boiling point of the various groups present in these by-products, it was estimated that when R is ethyl compounds A and B would boil about 20" above the desired alcohol, XI, while compound C would have about the same boiling point and compound D would boil about 40" above XI. Since the hydrocarbon, C, is inert, its presence in small amount in the desired alcohol is no disadvantage, for it is easily separated from the higher molecular weight compounds obtained later in the synthesis. The other compounds should be easily separated in an efficient half-meter fractionating column. This proved the case, and a sample of crystalline diol, A, was isolated from the fraction boiling about 20" above the desired alcohol, XI. When R is propyl, all products except A should boil 20" or more above X I I ; however, the diol, A should boil no more than 10-15" above XII. This proved to be the case, and the construction of a four-foot Podbielniak type column was necessary for efficient separation of this diol. When the saturated ester (XIII or XIV) is the desired product, separation of the products obtained by low-pressure hydrogenation must be considered. When R is octyl, the separation is simple, for all by-products differ in boiling point by 40" or more from the desired ester. When R is hexyl, the only separation problem concerns the unreacted keto ester, IX. This is reduced, in part, by platinum at low pressure to give the corresponding hydroxy ester, which was separated from the saturated ester, XIII, with difficulty, even in the four-

BRANCHED-CHAIN FATTY ACIDS.

141

IX

foot column. This difficulty was avoided, however, by fractional distillation of the unsaturated ester, before hydrogenation, for the keto ester, IX, boils a t least ten degrees below the corresponding hydroxy ester. Some loss of unsaturated ester may have occurred during the long heating necessary for fractional distillaition, for the yield of XI11 (39%) was appreciably lower than obtained for XIT' (55%). EXPERIMENTAL

Microanalyses are by C. W. Koch and V. H. Tashinian. All melting points are corrected; all boiling points are uncorrected. All distillations, unless otherwise specified, were carried out in a half-meter Podbielniak type column with heated jacket and partial reflux head. TABLE I KETO ESTERS

I ESTER

YIELD,

%

B.P..

'c

~ . H o n%

__-

I

-_ CALC'D

POUND C H ---

C

VI1 VI11

x

XV XVI

88-89 94.5 45" 74 72

169-173 165-167 211-212 235-240 236-240

ANAL.

H

68.68 68,96 73.12

10.86 10.52 11.28

c

76.03

12.31

The cJ-carbethoxycaprylyl chloride used in this preparation was prepared from an old sample of' half ester which had disproportionated (9) to considerable di-acid chloride and di-ester. The di-ester is inert, but the di-acid chloride yielded 9,17-heracosanedione, b.p. 247-248' (2 mm.); 19.7 g. isolated from an 0.33 mole run. After two crystallizations from acetone, this diketone melted at 92.8-93.4'. Anal. Calc'd for Cz6H4802: C, 78.88; H, 12.71. Found: C, 79.09; H, 12.88. b After two crystallizations from acetone, m.p. 38.2-38.7". c Not analyzed, characterized as acid, cf. Table 11. (1

Alkyl halides. The simple normal halides used a starting materials were purified commercial products or obtained from commercial alcohols by usual methods. All were distilled through the half-meter column or a 1-meter column packed with glass helices, and collected over a range of about one degree. Branched-chain bromides were prepared from anhydrous hydrogen bromide taken from a cylinder, following the usual procedure (8). 10-Ethyl-1.bromododecane was obtained in 83% yield, b.p. 159.5-161.5" (11 mm.), n: 1.4653. Anal. Calc'd for Ct4HzDBr:C, 60.66; H, 10.55. Found: C, 59.47; H, 10.80. 9-n-Propyl-1-bromododecanewas obtained in 63% yield, b.p. 168-171.5° (13 mm.), nz 1.4648. A n d . Calc'd for ClsHalBr: C, 61.84; H, 10.73. Found: C, 61.68; H, 10.93. Keto est8vswere prepared by the usual method (9) from dialkylcadmium reagent snd ester acid chloride and isolated as described previously for keto esters. Data for the products are found in Tables I and 11,yields being based on ester acid chloride. For esters, VII, VIII, and X, there were used two equivalents of alkyl halide (ethyl iodide, n-propyl bromide, and ro-octyl bromide) for one of ester acid chloride. For esters, XV and XVI, the equivalency of branched-chain halide was 1.25.

142

JAMES CASON .4ND W. L. STANLEY

Ethyl 18-ketooctadecanoate ( I X ) . A suspension of 200 g. (0.67 mole) of crude 12-hydroxyoctadecanoic acid (from saponification of commercial hydrogenated castor oil) in 1100 ml. of glacial acetic acid was stirred vigorously as there was added during two hours a solution of 50 g. (0.50mole) of chromic anhydride in 270 ml. of glacial acetic acid. The temperature of the mixture did not rise above 37". After stirring, without heating, had been continued for an additional two hours, the mixture was poured, with stirring, into ten liters of water. The solid product was crystallized from acetone, after treatment with Norit. The yield of pale lavender keto acid, m.p. 80.5-83", was 155 g. (is'%, assuming homogeneous starting material). The impure acid so obtained was esterified by heating for two hours with 450 ml. of absolute ethanol containing 24.5 g. of hydrogen chloride gas. After dilution of the reaction mixture with water and extraction with ether, the ester was distilled. hfter a fore-run of 15 g., consisting largely of ethyl stearate, the crystalline keto ester was collected at 199-200" (3.0 mm.), m.p. 35-37.5", wt. 132.2 g. (61% yield from crude hydroxy acid). Saponification of a sample of the ester and crystallization of the keto acid from acetone yielded lustrous blades, m.p. 82.0-82.3". Perrotte (11) reported m.p. 81.0-81.5'. 10-Ethyl-f-dodecanol ( X I ) . (A) A Grignard reagent was prepared in an atmosphere of nitrogen from 63 g. of ethyl iodide and 8.9 g. of magnesium in 200 ml. of ether. After about half the ether had been distilled, 500 ml. of dry thiophene-free benzene waa added

_ _ _ -__

__

ESTER

I

I

TABLE I1 DERIVATIVES OF KETO ESTERS

-_

DERIVATIVE

'

--

SOLVENT FOB CRYST.

Y.P.,

*C.

I

VI1 VI11

xv

'

,

Semicarbazone Keto acidb Keto acide

~

Acetone Hexane Acetone

,

74.6-75.80 55.9-56.4 67.0-67.8

Polymorphic, remelts at 79.5-81.0". Paraskova (10) reports m.p. 81.0-82.0'. *Mol. wt. found, 217.0 (calc'd 214.3). c Calc'd for C2,H4603: C, 75.30; H, 12.10. Found: C, 75.53; H, 12.40.

6

and the solution forced under nitrogen pressure into a separatory funnel. This solution waa added dropwise, during one hour, t o a stirred solution of 87.4 g. of ethyl 10-ketododecanoate (VII) in 450 ml. of benzene, the mixture being cooled in an ice-salt bath just insufficiently t o freeze the benzene. After addition was complete, stirring was continued for an additional twenty minutes, then the organometallic complex was decomposed with ice and acid. The organic layer and an additional benzene extract of the aqueous phase were washed with water, 5% sodium carbonate solution, water, and saturated sodium chloride solution. After solvent had been distilled, last traces in a vacuum, the residue was heated for one hour with a few crystals of iodine, at 180-190'. Distillation of the unsaturated esters from a Claisen flask yielded 75.3 g. of b.p. 164-170" (10 mm.). This distillate was hydrogenated with 15 g. of copper chromite catalyst (12) a t 250" and an initial cold pressure of 3180 lbs. per sq. in. The final pressure a t 250" was 2870 lbs., and hydrogenation was complete in 3 hrs., 10 mins. from the time shaker and heater were started. Distillation of the product at 10 mm. pressure gave the following fractions: (a)10-ethyl-ldodecanol, wt. 43.1 g., b.p. 155-160'; (b) intermediate fraction, wt. 2.1 g.; ( c ) 1,lO-dodecanediol, wt. 12.9 g., b.p. 174.5-175.5'. The yield of alcohol, XI, is 55%, based on keto ester. For the sample analyzed, ng 1.4487. A n a l . Calc'd for ClrIImO: C , 78.43; H, 11.11. Found: C, 77.82; H , 13.91. (B) A solution of ethylmagnesium iodide,prepared as inMethod (A) from 38 g. of ethyl iodide, was added during 80 minutes t o a stirred solution of 29.8 g. of w-carbethoxynonoyl chloride in 85ml. of benzene, with cooling in ice and salt. The reaction mixture was worked

BRANCHED-CHAIN FATTY ACIDS.

IX

143

up, and the unsaturated ester obtained and hydrogenated as above. Distillation of the product a t 10 mm. pressure gave the following fractions: (a) IO-ethyl-1-dodecanol, wt. 4.6 g., b.p. 153-158"; ( b ) intermediate; (c) 1,lO-dodecanediol, wt. 3.5 g., b.p. 172.5-173". Thus, the over-all yield of X I is only 18%. The phenylurethan of X I , after two crystallizations from hexane, melted a t 54-56.1". It is apparently polymorphic since a sample melted completely a t once when placed in a bath a t 55.5". Anal. Calc'd for C ~ I H ~ ~ NC,O75.63; ~ : H, 10.58. Found: C, 75.29; H, 10.26. 1 , 10-Dodecanediol, Frac. ( c ) , Method (A), after repeated crystallization from hexaneacetone, melted a t 38.6-39.8'. Anal. Calc'd for C1~H2602: C, 71.23; H, 12.95. Found: C, 71.16; H, 12.69. Ethyl 10-ethyldodecanoate was prepared by hydrogenation of 14.9 g. of unsaturated esters [obtained as in Method (A) above] a t room temperature and low pressure, with 0.3 g. of platinum oxide catalyst in 100 ml. of 95% ethanol. Hydrogenation was complete in 40 minutes, and distillation gave 11.4 g. (64% over-all yield from keto ester) of saturated ester, b.p. 162-163" (10mm.). 9-n-Propyl-1-dodecanol (XII) was prepared according t o Method (A) described for dcohol, XI. From 0.5 mole of ethyl 9-ketododecanoate and ca. 0.58 mole of n-propylmagnesium bromide, distillation through a 4-foot Podbielniak type column a t 4 mm. pressure of the products obtained after high-pressure hydrogenation gave the following fractions: (a) 9-n-propyl-1-dodecanol, wt. 54.3 g. (45.5%, over-all) b.p. 150-153', n: 1.4507; (b) intermediate, wt. 3.6 g.; (c) 1,9-dodecanediol, wt. 18.9 g., b.p. 167-172'. The alcohol, XII, was characterized as the a-naphthylurethan, which crystallized in nodular clusters from acetone and appears to be polymorphic. After four crystallizations, but complete melting occurred at once when the sample waa plsced the m.p. w , 51-57', ~ in a bath a t 55". Anal. Calc'd for C26HmNOt: N, 3.54. Found: N, 3.47. The 3,5-dinitrobenzoate of this alcohol is an oil and the pphenylbenroate is a lowmelting solid. I ,9-dodecanedioZ, Frac. (c) above, after repeated crystallization from hexane-acetone melted a t 38.2-38.8". Anal. (hlc'd for C I ~ H ~ ~C, O 71.23; P: H , 12.95. Found: C, 71.30; H, 13.13. Ethyl 1%'-n-hezyloctadecanoate ( X I I I ) . Starting with 0.12 mole of ethyl 12-ketooctadecanoate (IX) and the Grignard reagent from 0.21 mole of n-hexyl bromide, a mixture of unsaturated esters was prepared as described under Method (A) for IO-ethyl-1-dodecanol. The lower ratio of keto ester was used in order t o simplify the separation of this starting material. Distillation through the column of the mixture remaining after dehydration yielded 4.3 g. of fore-run and 33.1 g. (69% yield) of pale yellow unsaturated esters, b.p. 211-215" (2 mm.). There was 11 g. of distillation residue. The ester fraction was immediately hydrogenated a t room temperature and low pressure with 0.2 g. of platinum oxide catalyst in 125 ml. of 95% ethanol. The ester was sparingly soluble in ethanol and hydrogenation required 12 hours. After solution of the product in ether, removal of catalyst, and distillation of solvent, the ester was distilled; yield 18.5 g. (39%), b.p. 213-215" (2 mm.), n: 1.4508. Anal. Calc'd for Cz0H5202: C, 78.72; H, 13.21. Found: C, 78.58; H , 13.38. Ethyl 9-n-octylheptadecanoate (XZV) was prepared in the same manner as described for XI11 except, that the unsaturated esters were distilled from a Claisen flask. In a run starting with 0.067 mole of ethyl 9-ketoheptadecanoate and the Grignard reagent from 0.11 mole of n-ootyl bromide, the yield of crude unsaturated esters was 21.5 g. After hydrogenation as for X I I I , distillation yielded the following fractions: ( a ) fore-run, wt. 4.3 g.

144

JAMES CASON AND W. L. STANLEY

and containing 1.0 g. of ethyl 9-ketoheptadecanoate; ( b ) ethyl 9-n-octylheptadecanoate, wt. 15.3 g. (55% over-all yield), b.p. 224-227" (2 mm.), n: 1.4512. Anal. Calc'd for C27H~u02:C, 78.95; H, 13.26. Found: C, 78.98; H, 13.15. Ethyl 18-ethyloctadecanoate ( X V I I ) . Since the ethyl ester, IX, had been prepared in quantity, cyclohexyl 12-ketooctadecanoate was prepared by allowing a mixture of 61.5 g. (0.612 mole) of cyclohexanol, 50 g. (0.153 mole) of ethyl 12-ketooctadecanoate (IX), and 6.2 g. of hydrogen chloride gas t o stand at room temperature for eight days. Solvent was then removed in a vacuum, last traces a t 2.5 mm. and 180", and the residue (54.8 g . ) was used for the Grignard reaction. The Grignard reagent from 14.9 g. (0.095 mole) of ethyl iodide, in 50 ml. of ether and 110 ml. of benzene, was added dropwise t o a stirred solution of 30 g. (0.079 mole) of cyclohexyl 12-ketooctadecanoate in 110 ml. of benzene, the temperature being maintained by external Addition was completed in 15minutes, and five minutes later the mixture cooling at 5-10'. had become an unstirrable jelly, so stirring was continued for an additional 30 minutes at 25-30". The mixture was worked up and the hydroxy ester dehydrated as described under Method (A) for preparation of 10-ethyl-1-dodecanol (XI). The unsaturated esters, distilled from a Claisen flask, weighed 22.1 g. (7373, b.p. 213-220' (4 mm.). The unsaturated ester was immediately hydrogenated at low pressure and room temperature with 0.15 g. of platinum oxide catalyst in 150 ml. of 95% ethanol. Hydrogenation was complete in one hour. After catalyst had been removed by filtration, 100 ml. of absolute ethanol and 10.6 ml. of concentrated sulfuric acid were added, and the mixture was heated under reflux for 90 minutes. The ethyl ester, XVII, was isolated by dilution of the reaction mixture with water, extraction with benzene, and distillation; yield 14.5 g. (54% over-all), b.p. 191-194" (3 mm.), 1.4479. There was 2.5 g. of distillation residue, and the yield on the hydrogenation and trans-esterification step is probably subject t o improvement. Anal. Calc'd for C22H4402: c, 77.58; H, 13.02. Found: C, 77.33; H, 12.96. 20-Ethyldocosunoic acid ( I I I ) . The keto ester, XV, (23.8 g.) waa reduced by the Schneider and Spielman modification (6) of the Clemmensen method. The yield of eemi-solid ethyl 20-ethyldocosanoate was 15.2 g . (66%), b.p. 220-223" (ca. 1 mm.). Anal. Calc'd for CZ6H62Og:C, 78.72; H, 13.21. Found: C, 79.28; H, 13.86. By saponification of 19.1 g. of the ester and crystallization from acetone of the resultant acid, there was obtained 17.3 g. (93%) of 20-ethyldocosanoic acid, m.p. 60.542". After four additional crystallizations from hexane, the constant m.p. of 64.8-65.5' waa reached. Anal. Calc'd for C24H4&z: C, 78.17; H, 13.14; mol. wt., 368.7. Found: C, 78.53; H, 13.40; mol. wt., 369.0. For preparation of the amide, 0.7 g. of acid was allowed t o stand overnight with 0.45 g. of thionyl chloride then heated under reflux until no further gas evolution was apparent (ca. 45 mins.). Excess thionyl chloride was removed by heating in oacuo, and to the residual acid chloride there was added in one portion, with immediate shaking, IO ml. of icecold concentrated ammonium hydroxide. After filtration of the curdy precipitate and one crystallization from acetone, 0.65 g. of 80-ethyldocosanamide was obtained. After four additional crystallizations from acetone and two from hexane, the pure amide was obtained as fine white blades, m.p. 90.2-90.6'. Anal. Calc'd for C 2 J L N O : C, 78.40; H, 13.43. Found: C, 78.54; H, 13.55. For preparation of the tribromoanilide, the acid chloride, prepared as described above from 0.7 g. of acid, was heated for 2 hours on a steam-bath with 0.5 g. of 2,4,6-trobromoaniline. After one crystallization from ethanol, 0.8 g. of fine needles was obtained. After one additional crystallization from ethanol and three from benzene-hexane, the pure tribromoanilide was obtained, m.p. 104.7-105.3".

nt

BRANCHED-CHAIN FATTY ACIDS.

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145

Anal. Calc'd for Cc&BrtNO: C, 52.95; H, 7.41. Found: C, 53.17; H, 7.53. 18-n-Propylheneicosanoicacid ( I V ) . The keto ester, XVI, (27.9 9.) was reduced by the modified Wolff -Kishner method, following essentially the procedure of Huang-Minlon (13). After completion of the final heating period and acidification of the cooled and diluted reaction mixture, the precipitated acid was collected; wt. 14.6 g. (5801,), m.p. 4549". After four crystallizations from acetone, pure 18-n-propylheneicosanoicacid waa obtained as fine blades, m.p. 51.9-52.2'. Anal. Calc'd for C2;HasOz: C, 78.17; H, 13.14; mol. wt., 368.7. Found: C, 78.55; H, 13.23; mol. wt., 371.8. Derivatives of this acid were prepared as described for the isomer, 111. The amide, after two crystallizations from acetone, had the constant m.p. 82.1-82.4' Anal. Calc'd for CzaH&O: C, 78.40; H, 13.43. Found: C, 78.58; H, 13.12. The tribromoanilide, after four crystallizations from benzene-hexane, was obtained as very fine needles which grew in clusters at first and finally converted the solution into a gel, m .p. 911.6-93.6'. Anal. Calc'd for CJ&oBraNO: C, 52.95; H, 7.41. Found: C , 53.28; H, 7.43. 12-n-Hexyloctadecanoic acid ( V ) wm obtained by saponification of 17.4 g. of the ester, XIII. The crude acid (16.2 g.) was a liquid which set t o a solid on standing overnight. After two crystallizations from acetone, 7.7 g. of the pure acid was obtained as long needles, m.p. 28.3-28.7". AiLal. Calc'd for C24H4801:mol. wt., 368.7. Found: mol. wt., 368.0. The p-bromoanilide of this acid was prepared by heating a solution of 1.0 g. of p-bromoaniline and the acid chloride from 1.0 g. of acid in 10 ml. of benzene under reflux for 3 hours. The benzene solution was washed with water, dilute hydrochloric acid, water, and sodium bicarbonate solution, then the benzene was distilled. The residue was crystallized twice from hexane (Norit), in which solvent i t forms a gel, and twice from methanol. The pure anilide separated from methanol in spherical burrs of needles, m.p. 67.2-67.8". Anal. Calc'd for CaoHsABrNO: C, 68.94; H, 10.03. Found: C, 68.95; H, 9.96. 9-n-Octylheptadecanoic acid ( V I ) was obtained in 12 g. yield by saponification of 13.7 g. of the ester, XIV. The crude acid was a viscous liquid which crystallized in an ice-salt bath. It was crystallized twice from acetone, cooling t o about -30". After the second crystallization, the crystals were washed with acetone cooled to -70', and the funnel was placed in a desiccator which was immediately evacuated. Evaporation of acetone prevented melting until nearly all solvent was removed, and the oil was left a t about 1 mm. pressure for five days. The recrystallized acid, on chilling and being allowed t o warm up, melted a t 9-14', n; 1.4585. Anal. Calc'd for Cz6H6002:mol. wt., 382.9. Found: mol. wt., 381.5, 381.2. The p .bromoanilide, prepared as described for acid, V, after three crystallizations from acetone, was obtained as burrs of fine needles, m.p. 79.7-80.1'. -4nal. Calc'd for CaxHbrBrNO: C, 69.36; H, 10.13. Found: C, 69.04; H, 9.80. The amide and tribromortnilide of the acid could not be obtained as satisfactory crystalline derivatives. SUMMART

Four new acids with symmetrical end-groups have been prepared. The branching groups were, respectively, ethyl, n-propyl, n-hexyl, and n-octyl. As the end-group became larger, causing the tertiary carbon to approach the middle of the chain, the melting point dropped further below that of the normal

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JAMES CASON AND

W. L. STANLEY

isomer. This behavior is the same type as that observed when a branching methyl group is moved toward the middle of the chain; hence a symmetrical end-group has no tendency to impart to branched-chain acids a relatively high melting point. In the course of these syntheses, the selective reaction of a Grignard reagent with the keto group in an aliphatic keto ester has been studied, and improved yields have been realized in this reaction. BERKELEY,CALIFORNIA REFERENCES

(1) PROUTAND CASON,J . Org. Chem., preceding article. (2) CHARGAFF, Ber., 66, 745 (1932). SUTHERLAND, AND CORBY, J . A m . Chem. SOC.,64,691 (1942). (3) WHITMORE, (4) CASON,J . Org. Chem., 13, 227 (1948). (5) STALLBERG-STENHAGEN AND STENHAGEN, J . Biol. Chem., 166, 599 (1946). (6) SCENEIDER AND SPIELMAN, J . Biol. Chem., 142, 345 (1942). CASONAND PROUT,J . Am. Chem. SOC.,66,46 (1944). (7) CASON,ADAMS,BENNETT,AND REGISTER, J . A m . Chem. SOC.,66, 1764 (1944): CASON,BREWER, AND PIPPEN,J . Org. Chem., 13, 239 (1948). AND BURNETT, Org. Syn., Coll. Vol. 11, 246 (1943). (8) REID,RUEIOFF, (9) CASON,J . Am. Chem. SOC.,68, 2078 (1946). Compt. rend., 198, 1701 (1934). (10) PARASKOVA, (11) PERROTTE, Compt. rend., 200,746 (1935). (12) ADKINS,Org. Syn., Coll. Vol. 11, 144 (1943). (13) HUANG-MINLON, J . Am. Chem. SOC.,68, 2487 (1946).